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Age-related macular degeneration (AMD) is a leading cause of vision impairment in people over 50 years of age and has a great impact on quality of life as it affects central vision. Although there have been treatments available for the neovascular form of late AMD for decades, until now there have not been treatments available for the atrophic form of late AMD - geographic atrophy (GA). Recently, treatments acting on the complement pathway have been approved by the United States Food and Drug Administration, with other jurisdictions such as Australia considering their approval. Furthermore, there are many more potential treatments for GA currently in clinical trials. However, unlike the treatments for neovascular AMD, where clinicians have treated virtually all patients presenting with exudation, the decision to treat those with GA will be more nuanced and individualised. Longitudinal retinal imaging will be one important asset that will help tremendously when counselling patients, as through these images, the growth pattern of the atrophy can be determined. Even without individual prior imaging history, there are other imaging clues to help predict growth rates and threats to the fovea, and hence imminent vision loss. Optometrists have a critical role in this new era where GA treatments will be available, as they are often the first to have contact with GA patients. Insightful, well-informed counselling and appropriate referral for those seeking more information on potential treatment to confirm the diagnosis and perform baseline imaging at a location likely to undertake any future treatment will ensure that appropriate patients have had the best workup to be individually managed once these treatments arrive in Australia.

Aims: To report the outcomes of patients with neovascular age-related macular degeneration (nAMD) at Palmerston North Eye Clinic (PNEC) during 2020 and 2021, comparing time to treatment initiation based on nurse-injector availability and during COVID-19 restrictions., Methods: Data were recorded from a prospective database for patients with nAMD at PNEC. Each patient's electronic health record was reviewed to ensure the accuracy of the database and to fill in missing data points. Statistics were done using Microsoft Excel and R., Results: One hundred and fifty-six eyes were diagnosed with nAMD during the study. Mean time from referral triage to first injection was 13.08 days across the study period. Time to treatment initiation was not statistically different by level of COVID-19 restriction but there was a significant difference in first specialist appointment to injection interval when three nurse-injectors were available compared to four. The effect seemed most evident in subsequent months after reduced nurse-injector availability began., Conclusions: Despite an increase in nAMD diagnoses each year, PNEC continues to meet national guidelines for interval from referral to treatment initiation through innovations in practice. As demand for intravitreal injections continues to increase, further resourcing and research into newer agents will be required to keep wait times compliant with guidelines., Competing Interests: Nil., (© PMA.)

Subretinal injection (SR injection) is a commonly used method of ocular drug delivery and has been mainly applied for the treatment of neovascular age-associated macular degeneration (nAMD) and sub-macular hemorrhage (SMH) caused by nAMD, as well as various types of hereditary retinopathies (IRD) such as Stargardt's disease (STGD), retinitis pigmentosa (RP), and a series of fundus diseases such as Leber's congenital dark haze (LCA), choroidal defects, etc. The commonly used carriers of SR injection are mainly divided into viral and non-viral vectors. Leber's congenital amaurosis (LCA), choroidal agenesis, and a series of other fundus diseases are also commonly treated using SR injection. The commonly used vectors for SR injection are divided into two categories: viral vectors and non-viral vectors. Viral vectors are a traditional class of SR injection drug carriers that have been extensively studied in clinical treatment, but they still have many limitations that cannot be ignored, such as poor reproduction efficiency, small loading genes, and triggering of immune reactions. With the rapid development of nanotechnology in the treatment of ocular diseases, nanovectors have become a research hotspot in the field of non-viral vectors. Nanocarriers have numerous attractive properties such as low immunogenicity, robust loading capacity, stable structure, and easy modification. These valuable features imply greater safety, improved therapeutic efficacy, longer duration, and more flexible indications. In recent years, there has been a growing interest in nanocarriers, which has led to significant advancements in the treatment of ocular diseases. Nanocarriers have not only successfully addressed clinical problems that viral vectors have failed to overcome but have also introduced new therapeutic possibilities for certain classical disease types. Nanocarriers offer undeniable advantages over viral vectors. This review discusses the advantages of subretinal (SR) injection, the current status of research, and the research hotspots of gene therapy with viral vectors. It focuses on the latest progress of nanocarriers in SR injection and enumerates the limitations and future perspectives of nanocarriers in the treatment of fundus lesions. Furthermore, this review also covers the research progress of nanocarriers in the field of subretinal injection and highlights the value of nanocarrier-mediated SR injection in the treatment of fundus disorders. Overall, it provides a theoretical basis for the application of nanocarriers in SR injection., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Guan et al.)

Neovascular age-related macular degeneration (nAMD) causes severe visual impairment. Pigment epithelium-derived factor (PEDF), soluble CD59 (sCD59), and soluble fms-like tyrosine kinase-1 (sFLT-1) are potential therapeutic agents for nAMD, which target angiogenesis and the complement system. Using the AAV2/8 vector, two bi-target gene therapy agents, AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59, were generated, and their therapeutic efficacy was investigated in laser-induced choroidal neovascularization (CNV) and Vldlr -/- mouse models. After a single injection, AAV2/8-mediated gene expression was maintained at high levels in the retina for two months. Both AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59 significantly reduced CNV development for an extended period without side effects and provided efficacy similar to two injections of current anti-vascular endothelial growth factor monotherapy. Mechanistically, these agents suppressed the extracellular signal-regulated kinase and nuclear factor-κB pathways, resulting in anti-angiogenic activity. This study demonstrated the safety and long-lasting effects of AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59 in CNV treatment, providing a promising therapeutic strategy for nAMD., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose of Review: This review highlights treatment options, both under investigation and currently available, for the treatment of dry age-related macular degeneration (AMD). An update on current clinical studies for dry AMD has been summarized., Recent Findings: Advanced dry AMD, characterized by geographic atrophy (GA), is a leading cause of blindness in the developed world, though prior to 2023 there was no approved treatment. There are now two approved treatments in the United States for GA. Additionally, there are several studies and trials to investigate therapeutic potential and effects of therapies for earlier intervention in dry AMD. Approaches to therapy include inhibiting the complement system, utilizing gene therapy, stem cell therapy, laser therapy, and surgical implants., Summary: While there has been notable prior advancement in the treatment for neovascular or wet AMD, for the first time there are Food and Drug Administration (FDA) approved treatments for GA. Clinical studies have shown promise for additional methods for managing dry AMD both medically and surgically., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss among the elderly in Western communities, with an estimated global prevalence of 10 - 20% in people older than 65 years. AMD leads to central vision loss due to degeneration of the photoreceptors, retinal pigment epithelium and the choriocapillaris. Beckman's classification for AMD, based upon color fundus photographs, divides the disease into early, intermediate, and late forms. The late, vision-threatening stage includes both neovascular AMD and geographic atrophy. Despite its high prevalence and impact on patients' quality of life, treatment options for AMD are limited. While neovascular AMD can be medically managed with anti-VEGF intravitreal injections, until very recently there has been no approved treatment options for atrophic AMD; however, in February 2023 the first treatment for geographic atrophy - pegcetacoplan - was approved by the US FDA. We describe the current landscape of potential gene and cell therapeutic strategies for late-stage AMD, with an emphasis on the therapeutic options that might become available in the next few years., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be consideredas potential competing interests: LNA: Consultant: Apellis, Novartis. Investigator: Gyroscope, Belite, Nacuity, Janssen. RHG consultant Apellis, Novartis Roche, Genentech, Bayer.: TLE: Consultant: Novartis. Investigator: Gyroscope, Belite, Nacuity, Janssen. DCS - Co-investigator: Gyroscope, Belite, Nacuity, Janssen., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Stargardt disease, one of the most common forms of inherited retinal diseases, affects individuals worldwide. The primary cause is mutations in the ABCA4 gene, leading to the accumulation of toxic byproducts in the retinal pigment epithelium (RPE) and subsequent photoreceptor cell degeneration. Over the past few years, research on Stargardt disease has advanced significantly, focusing on clinical and molecular genetics. Recent studies have explored various innovative therapeutic approaches, including gene therapy, stem cell therapy, and pharmacological interventions. Gene therapy has shown promise, particularly with adeno-associated viral (AAV) vectors capable of delivering the ABCA4 gene to retinal cells. However, challenges remain due to the gene's large size. Stem cell therapy aims to replace degenerated RPE and photoreceptor cells, with several clinical trials demonstrating safety and preliminary efficacy. Pharmacological approaches focus on reducing toxic byproduct accumulation and modulating the visual cycle. Precision medicine, targeting specific genetic mutations and pathways, is becoming increasingly important. Novel techniques such as clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 offer potential for directly correcting genetic defects. This review aims to synthesize recent advancements in understanding and treating Stargardt disease. By highlighting breakthroughs in genetic therapies, stem cell treatments, and novel pharmacological strategies, it provides a comprehensive overview of emerging therapeutic options.

Introduction: Neovascular age-related macular degeneration (nAMD) represents a leading cause of severe visual impairment in individuals over 50 years of age in developed nations. Intravitreal anti-vascular endothelial growth factor (VEGF) injections have become the standard of care for treating nAMD; however, monthly or bimonthly dosing represents significant time and cost burden due to the disease's chronic nature and limited medication half-life., Areas Covered: This review summarizes innovative therapeutics and delivery methods for nAMD. Emerging methods for extended drug delivery include high molar concentration anti-VEGF drugs, intravitreal sustained-release polymers and devices, reservoirs for intravitreal delivery, suprachoroidal delivery of small molecular suspensions and gene therapy biofactories. In addition to VEGF-A, therapies targeting inhibition of VEGF-C and D, the angiopoetin-2 (Ang-2)/Tie-2 pathway, tyrosine kinases, and integrins are reviewed., Expert Opinion: The evolving therapeutic landscape of nAMD is rapidly expanding our toolkit for effective and durable treatment. Recent FDA approvals of faricimab (Vabysmo) and high-dose aflibercept (Eylea HD) for nAMD with potential extension of injection intervals up to four months have been promising developments for patients and providers alike. Further research and innovation, including novel delivery techniques and pharmacologic targets, is necessary to validate the efficacy of developing therapeutics and characterize real-world outcomes, demonstrating promise in expanding treatment durability.

Artificial intelligence (AI) has demonstrated revolutionary potential and wide-ranging applications in the comprehensive management of fundus diseases, yet it faces challenges in clinical translation, data quality, algorithm interpretability, and cross-cultural adaptability. AI has proven effective in the efficient screening, accurate diagnosis, personalized treatment recommendations, and prognosis prediction for conditions such as diabetic retinopathy, age-related macular degeneration, and other fundus diseases. However, there is a significant gap between the need for large-scale, high-quality, and diverse datasets and the limitations of current research data. Additionally, the black-box nature of AI algorithms, the acceptance by clinicians and patients, and the generalizability of these algorithms pose barriers to their widespread clinical adoption. Researchers are addressing these challenges through approaches such as federated learning, standardized data collection, and prospective trials to enhance the robustness, interpretability, and practicality of AI systems. Despite these obstacles, the benefits of AI in fundus disease management are substantial. These include improved screening efficiency, support for personalized treatment, the discovery of novel disease characteristics, and the development of precise treatment strategies. Moreover, AI facilitates the advancement of telemedicine through 5G and the Internet of Things. Future research should continue to tackle existing issues, fully leverage the potential of AI in the prevention and treatment of fundus diseases, and advance intelligent, precise, and remote ophthalmic services to meet global eye health needs.

In previous animal model studies, we demonstrated the potential of rAAV2-sVEGFRv-1, which encodes a truncated variant of the alternatively spliced soluble version of VEGF receptor-1 (VEGFR1), as a human gene therapy for age-related macular degeneration (AMD) and diabetic retinopathy (DR). Here, we elucidate in vitro some of the mechanisms by which rAAV2-sVEGFRv-1 exerts its therapeutic effects. Human umbilical vein endothelial cells (HUVECs) were infected with rAAV2-sVEGFRv-1 or a control virus vector in the presence of members of the VEGF family to identify potential binding partners via ELISA, which showed that VEGF-A, VEGF-B, and placental growth factor (PlGF) are all ligands of its transgene product. In order to determine the effects of rAAV2-sVEGFRv-1 on cell proliferation and permeability, processes that are important to the progression AMD and DR, HUVECs were infected with the therapeutic virus vector under the stimulation of VEGF-A, the major driver of the neovascularization that characterizes the forms of these conditions most associated with vision loss. rAAV2-sVEGFRv-1 treatment, as a result, markedly reduced the extent to which these processes occurred, with the latter determined by measuring zonula occludens 1 expression. Finally, the human microglial HMC3 cell line was used to show the effects of the therapeutic virus vector upon inflammatory processes, another major contributor to angiogenic eye disease pathophysiology, with rAAV2-sVEGFRv-1 reducing therein the secretion of pro-inflammatory cytokines interleukin (IL)-1β and IL-6. Combined with our previously published in vivo data, the in vitro activity of the expressed transgene here further demonstrates the great promise of rAAV2-sVEGFRv-1 as a potential human gene therapeutic for addressing angiogenic ocular conditions., Competing Interests: S.Y.M., H.J.K., J.K.K., J.K., J.-S.C., S.-Y.W., K.P., and S.H.S.L. are employees of CdmoGen Co., Ltd., in which K.P. and S.H.S.L. have personal financial interests. No other potential conflicts of interest relevant to this article were reported. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Moon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Degeneration of the macula is associated with several overlapping diseases including age-related macular degeneration (AMD) and Stargardt Disease (STGD). Mutations in ATP Binding Cassette Subfamily A Member 4 (ABCA4) are associated with late-onset dry AMD and early-onset STGD. Additionally, both forms of macular degeneration exhibit deposition of subretinal material and photoreceptor degeneration. Retinoic acid related orphan receptor α (RORA) regulates the AMD inflammation pathway that includes ABCA4, CD59, C3 and C5. In this translational study, we examined the efficacy of RORA at attenuating retinal degeneration and improving the inflammatory response in Abca4 knockout (Abca4 -/- ) mice. AAV5-hRORA-treated mice showed reduced deposits, restored CD59 expression and attenuated amyloid precursor protein (APP) expression compared with untreated eyes. This molecular rescue correlated with statistically significant improvement in photoreceptor function. This is the first study evaluating the impact of RORA modifier gene therapy on rescuing retinal degeneration. Our studies demonstrate efficacy of RORA in improving STGD and dry AMD-like disease., (© 2024. The Author(s).)

Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment among people aged 50 years and older. Earlier research has indicated that the communication process between patients and healthcare professionals (HCPs) leaves considerable room for improvement in AMD care. Effective communication is essential to enhance trust in the professional and understanding of the diagnosis and treatment, and decrease anxiety and stress related to illness. We review patients' experiences, needs and preferences regarding information provision, communication style of the HCP and shared decision-making. We conducted a systematic search in PubMed, Embase, PsycINFO, CINAHL and Web of Science. Study quality was assessed using standard checklists of quality measures. Our search returned 31 eligible articles. Findings indicated current deficits in information provision for people with AMD. Patients were often ill-informed regarding the chronic character of the condition, treatment duration, nutrition, and visual aids and low vision rehabilitation. Many patients were not actively involved during the decision-making process. Altogether, patients with AMD are faced with challenges in terms of patient-HCP communication. Methods of providing information and discussing possible options for care need to be further investigated and improved for this patient group., Competing Interests: Declaration of Competing Interest none., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Age-related macular degeneration (AMD) is a significant factor contributing to serious vision loss in adults above 50. The presence of posterior segment barriers serves as chief roadblocks in the delivery of drugs to treat AMD. The conventional treatment strategies use is limited due to its off-targeted distribution in the eye, shorter drug residence, poor penetration and bioavailability, fatal side effects, etc. The above-mentioned downside necessitates drug delivery using some cutting-edge technology including diverse nanoparticulate systems and microneedles (MNs) which provide the best therapeutic delivery alternative to treat AMD efficiently. Furthermore, cutting-edge treatment modalities including gene therapy and stem cell therapy can control AMD effectively by reducing the boundaries of conventional therapies with a single dose. This review discusses AMD overview, conventional therapies for AMD and their restrictions, repurposed therapeutics and their anti-AMD activity through different mechanisms, and diverse barriers in drug delivery for AMD. Various nanoparticulate-based approaches including polymeric NPs, lipidic NPs, exosomes, active targeted NPs, stimuli-sensitive NPs, cell membrane-coated NPs, inorganic NPs, and MNs are explained. Gene therapy, stem cell therapy, and therapies in clinical trials to treat AMD are also discussed. Further, bottlenecks of cutting-edge (nanoparticulate) technology-based drug delivery are briefed. In a nutshell, cutting-edge technology-based therapies can be an effective way to treat AMD., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Age-related macular degeneration (AMD) stands as a leading cause of irreversible blindness, particularly affecting central vision and impeding daily tasks. This paper provides a thorough exploration of AMD, distinguishing between its two main subtypes-Wet and Dry AMD-while shedding light on the prevalence and risk factors, including age, genetics, and smoking. The focus shifts to the current and future treatment landscape, examining both Dry and Wet AMD. Regarding Dry AMD, interventions such as antioxidant supplementation and ongoing clinical trials offer hope. Notable among these is Pegcetacoplan which is the only Food and Drug Administration (FDA)-approved medication, displaying promising results in reducing geographic atrophy lesions. For Wet AMD, anti-Vascular Endothelial Growth Factor therapies like Ranibizumab (Lucentis®) have been instrumental, and newer drugs like Faricimab and OPT-302 show comparable efficacy with extended dosing intervals. Additionally, gene therapies such as RGX-314 present a potential paradigm shift, reducing or eliminating the need for frequent injections. Biosimilars offer cost-effective alternatives. The paper also delves into the integration of technology and artificial intelligence in AMD management, highlighting the role of smartphone apps for patient monitoring and artificial intelligence algorithms for diagnosis and surveillance. Furthermore, patient perspectives on artificial intelligence demonstrate a positive correlation between understanding and trust. The narrative concludes with a glimpse into ground-breaking technologies, including retinal implants and bionic chips, offering hope for vision restoration. Overall, this paper underscores the multifaceted approach in addressing AMD, combining traditional and innovative strategies, paving the way for a more promising future in AMD treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Age-related macular degeneration (AMD) affects quality of life and independence, and its incidence and prevalence are increasing due to ageing of the population. Access to effective timely treatment can improve vision and reduce incidence of blindness. This study aimed to explore the perspectives of ophthalmologists in the Israeli public healthcare system regarding timely treatment of AMD patients., Methods: Qualitative semi-structured interviews were conducted in 2020-2021 with 22 senior ophthalmologists, from 10 general hospitals and from two HMOs, representing different geographic regions. All interviewees specialize in retinal diseases and work with AMD patients. Interviews discussed patient pathways involved in the diagnosis and treatment of AMD, access to care, and obstacles to timely care. Thematic analysis was conducted., Results: Based on the interviews, we describe the usual referral and treatment pathways. Themes included regional disparities, long wait times in some areas, a lack of retina specialists, differences in referral pathways, inappropriate use of emergency department to obtain timely treatment, and second-line treatment not fully covered by insurance, most affecting the weakest segments of the population., Conclusions: Loss of vision incurs high health and societal costs. In the context of insufficient medical manpower in Israel, the healthcare system will need to assess future resources to cope with accumulating burden of AMD cases over time in an ageing population. Precise referral information, and simultaneous referral to imaging and retinal clinics, may minimize delays in treatment. Awareness of AMD symptoms and the importance of early intervention could be highlighted by campaigns, particularly among high-risk groups., Highlights: • Interviews with hospital-based and community ophthalmologists showed regional disparities in AMD treatment, with long wait times and a lack of retina specialists in some areas. • Differences in referral pathways, inappropriate use of emergency department to obtain timely treatment, and second line treatment not fully covered by insurance were highlighted. • The healthcare system will need to assess future resources to cope with accumulating burden of AMD cases over time in an ageing population • Precise referral information, and simultaneous referral to imaging and retinal clinics, may minimize delays in treatment. • Awareness of AMD symptoms and the importance of early intervention should be emphasized in high-risk groups., (© 2024. The Author(s).)

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of rare conditions leading to various degrees of visual handicap and to progressive blindness in more severe cases. Besides visual rehabilitation, educational, and socio-professional support, there are currently limited therapeutic options, but the approval of the first gene therapy product for RPE65 -related IRDs raised hope for therapeutic innovations. Such developments are facing obstacles intrinsic to the disease and the affected tissue including the extreme phenotypic and genetic variability of IRDs and the fine tuning of visual processing through the complex architecture of the postmitotic neural retina. A precise phenotypic characterization is required prior to genetic testing, which now relies on high-throughput sequencing. Their challenges will be discussed within this article as well as their implications in clinical trial design., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Gene therapy holds promise as a transformative approach in the treatment landscape of age-related macular degeneration (AMD), diabetic retinopathy (DR), and diabetic macular edema (DME), aiming to address the challenges of frequent intravitreal anti-vascular endothelial growth factor (VEGF) injections. This manuscript reviews ongoing gene therapy clinical trials for these disorders, including ABBV-RGX-314, ixoberogene soroparvovec (ixo-vec), and 4D-150. ABBV-RGX-314 utilizes an adeno-associated virus (AAV) vector to deliver a transgene encoding a ranibizumab-like anti-VEGF antibody fragment, demonstrating promising results in Phase 1/2a and ongoing Phase 2b/3 trials. Ixo-vec employs an AAV2.7m8 capsid for intravitreal delivery of a transgene expressing aflibercept, showing encouraging outcomes in Phase 1 and ongoing Phase 2 trials. 4D-150 utilizes an evolved vector to express both aflibercept and a VEGF-C inhibitory RNAi, exhibiting positive interim results in Phase 1/2 studies. Other therapies reviewed include EXG102-031, FT-003, KH631, OLX10212, JNJ-1887, 4D-175, and OCU410. These therapies offer potential advantages of reduced treatment frequency and enhanced safety profiles, representing a paradigm shift in management towards durable and efficacious cellular-based biofactories. These advancements in gene therapy hold promise for improving outcomes in AMD and addressing the complex challenges of DME and DR, providing new avenues for the treatment of diabetic eye diseases.

Background Aims: Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, offer groundbreaking therapeutic potential for degenerative diseases and cellular repair. Despite their significance, a comprehensive bibliometric analysis in this field, particularly in relation to age-related macular degeneration (AMD), is yet to be conducted. This study aims to map the foundational and emerging areas in stem cell and AMD research through bibliometric analysis., Methods: This study analyzed articles and reviews on stem cells and AMD from 2000 to 2022, sourced from the Web of Science Core Collection. We used VOSviewer and CiteSpace for analysis and visualization of data pertaining to countries, institutions, authors, journals, references and key words. Statistical analyses were conducted using R language and Microsoft Excel 365., Results: In total, 539 publications were included, indicating an increase in global literature on stem cells and AMD from 2000 to 2022. The USA was the leading contributor, with 239 papers and the highest H-index, also the USA had the highest average citation rate per article (59.82). Notably, 50% of the top 10 institutions were from the USA, with the University of California system being the most productive. Key authors included Masayo Takahashi, Michiko Mandai, Dennis Clegg, Pete J. Coffey, Boris Stanzel, and Budd A. Tucker. Investigative Ophthalmology & Visual Science published the majority of relevant papers (n = 27). Key words like "clinical trial," "stem cell therapy," "retinal organoid," and "retinal progenitor cells" were predominant., Conclusions: Research on stem cells and AMD has grown significantly, highlighting the need for increased global cooperation. Current research prioritizes the relationship between "ipsc," "induced pluripotent stem cell," "cell culture," and "human embryonic stem cell." As stem cell culture and safety have advanced, focus has shifted to prognosis and complications post-transplantation, signifying the movement of stem cell research from labs to clinical settings., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Age-related macular degeneration (AMD) is a progressive neurodegeneration disease that causes photoreceptor demise and vision impairments. In AMD pathogenesis, the primary death of retinal neurons always leads to the activation of resident microglia. The migration of activated microglia to the ongoing retinal lesion and their morphological transformation from branching to ameboid-like are recognized as hallmarks of AMD pathogenesis. Activated microglia send signals to Müller cells and promote them to react correspondingly to damaging stimulus. Müller cells are a type of neuroglia cells that maintain the normal function of retinal neurons, modulating innate inflammatory responses, and stabilize retinal structure. Activated Müller cells can accelerate the progression of AMD by damaging neurons and blood vessels. Therefore, the crosstalk between microglia and Müller cells plays a homeostatic role in maintaining the retinal environment, and this interaction is complicatedly modulated. In particular, the mechanism of mutual regulation between the two glia populations is complex under pathological conditions. This paper reviews recent findings on the crosstalk between microglia and Müller glia during AMD pathology process, with special emphasis on its therapeutic potentials.

Recombinant adeno-associated viruses (rAAVs) have emerged as promising gene therapy vectors due to their proven efficacy and safety in clinical applications. In non-human primates (NHPs), rAAVs are administered via suprachoroidal injection at a higher dose. However, high doses of rAAVs tend to increase additional safety risks. Here, we present a novel AAV capsid (AAVv128), which exhibits significantly enhanced transduction efficiency for photoreceptors and retinal pigment epithelial (RPE) cells, along with a broader distribution across the layers of retinal tissues in different animal models (mice, rabbits, and NHPs) following intraocular injection. Notably, the suprachoroidal delivery of AAVv128-anti-VEGF vector completely suppresses the Grade IV lesions in a laser-induced choroidal neovascularization (CNV) NHP model for neovascular age-related macular degeneration (nAMD). Furthermore, cryo-EM analysis at 2.1 Å resolution reveals that the critical residues of AAVv128 exhibit a more robust advantage in AAV binding, the nuclear uptake and endosome escaping. Collectively, our findings highlight the potential of AAVv128 as a next generation ocular gene therapy vector, particularly using the suprachoroidal delivery route., (© 2024. The Author(s).)

Introduction: Patients with advanced age-related macular degeneration (AMD) frequently experience loss to follow-up (LTFU), heightening the risk of vision loss from treatment delays. This study aimed to identify factors contributing to LTFU in patients with advanced AMD and assess the effectiveness of telephone-based outreach in reconnecting them with eye care., Methods: A custom reporting tool identified patients with advanced AMD who had not returned for eye care between 31 October 2021 and 1 November 2022. Potentially LTFU patients were enrolled in a telephone outreach programme conducted by a telehealth extender to encourage their return for care. Linear regression analysis identified factors associated with being LTFU and likelihood of accepting care post-outreach., Results: Out of 1269 patients with advanced AMD, 105 (8.3%) did not return for recommended eye care. Patients LTFU were generally older (89.2 ± 8.9 years vs. 87.2 ± 8.5 years, p = 0.02) and lived farther from the clinic (25 ± 43 miles vs. 17 ± 30 miles, p = 0.009). They also had a higher rate of advanced dry AMD (26.7% vs. 18.5%, p = 0.04) and experienced worse vision in both their better-seeing (0.683 logMAR vs. 0.566 logMAR, p = 0.03) and worse-seeing (1.388 logMAR vs. 1.235 logMAR, p = 0.04) eyes. Outreach by a telehealth extender reached 62 patients (59%), 43 through family members or healthcare proxies. Half of the cases where a proxy was contacted revealed that the patient in question had died. Among those contacted directly, one third expressed willingness to resume eye care (20 patients), with 11 scheduling appointments (55%). Despite only two patients returning for in-person eye care through the intervention, the LTFU rate halved to 4.4% by accounting for those patients who no longer needed eye care at the practice., Conclusions: There is a substantial risk that older patients with advanced AMD will become LTFU. Targeted telephone outreach can provide a pathway for vulnerable patients to return to care., (© 2024 College of Optometrists.)

Age-related macular degeneration (AMD) is the most common cause of untreatable blindness in the developed world. Recently, CDHR1 has been identified as the cause of a subset of AMD that has the appearance of the "dry" form, or geographic atrophy. Biallelic variants in CDHR1-a specialized protocadherin highly expressed in cone and rod photoreceptors-result in blindness from shortened photoreceptor outer segments and progressive photoreceptor cell death. Here we demonstrate long-term morphological, ultrastructural, functional, and behavioral rescue following CDHR1 gene therapy in a relevant murine model, sustained to 23-months after injection. This represents the first demonstration of rescue of a monogenic cadherinopathy in vivo. Moreover, the durability of CDHR1 gene therapy seems to be near complete-with morphological findings of the rescued retina not obviously different from wildtype throughout the lifespan of the mouse model. A follow-on clinical trial in patients with CDHR1-associated retinal degeneration is warranted. Hypomorphic CDHR1 variants may mimic advanced dry AMD. Accurate clinical classification is now critical, as their pathogenesis and treatment are distinct., Competing Interests: Declaration of interests I.H.Y., M.E.M., R.E.M., and P.C.I. are named inventors on a patent for CDHR1 gene therapy owned and filed by the University of Oxford, and act as paid consultants to Beacon Therapeutics. R.E.M. is a director of Beacon Therapeutics., (Copyright © 2024. Published by Elsevier Inc.)

Purpose of Review: This review presents an update on completed stem cell therapy trials aimed at retinal diseases., Recent Findings: In recent years, several clinical trials have been conducted examining the safety and role of cell therapy in diseases, including age-related macular degeneration, Stargardt's macular dystrophy, and retinitis pigmentosa. Studies have utilized a variety of cell lines, modes of delivery, and immunosuppressive regimens. The prevalence of fraudulent cell therapy clinics poses threats to patients., Summary: Clinical trials have begun to characterize the safety of cell therapy in retinal disease. While studies have described the potential benefits of cell therapy, larger studies powered to evaluate this efficacy are required to continue progressing toward preventing retinal disease. Nonapproved cell therapy clinics require regulation and patient education to avoid patient complications., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Age-related macular degeneration and retinitis pigmentosa are degenerative retinal diseases that cause severe vision loss. Early clinical trials involving transplantation of photoreceptors as treatment for these conditions are underway. In this review, we summarize recent progress in the field of photoreceptor transplantation, including some pertinent results regarding photoreceptor manufacture, photoreceptor transplantation, mechanisms of donor-host cell integration such as material transfer and photoreceptor transplant immunology. We conclude by proposing several approaches that may provide a rational basis for selecting a vision restoration strategy (eg, donor-host synapse formation vs donor-host nanotube formation) and improved transplant efficiency., (© The Author(s) 2024. Published by Oxford University Press.)

Age-related macular degeneration and retinitis pigmentosa are degenerative retinal diseases that cause severe vision loss. Early clinical trials involving transplantation of retinal pigment epithelial cells and/or photoreceptors as a treatment for these conditions are underway. In this review, we summarize recent progress in the field of retinal pigment epithelium transplantation, including some pertinent clinical trial results as well as preclinical studies that address issues of transplant immunology, cell delivery, and cell manufacturing., (© The Author(s) 2024. Published by Oxford University Press.)

Pathogenic variants in ABCA4 are the underlying molecular cause of Stargardt disease (STGD1), an autosomal recessive macular dystrophy characterized by a progressive loss of central vision. Among intronic ABCA4 variants, c.4253+43G>A is frequently detected in STGD1 cases and is classified as a hypomorphic allele, generally associated with late-onset cases. This variant was previously reported to alter splicing regulatory sequences, but the splicing outcome is not fully understood yet. In this study, we attempted to better understand its effect on splicing and to rescue the aberrant splicing via antisense oligonucleotides (AONs). Wild-type and c.4253+43G>A variant-harboring maxigene vectors revealed additional skipping events, which were not previously detected upon transfection in HEK293T cells. To restore exon inclusion, we designed a set of 27 AONs targeting either splicing silencer motifs or the variant region and screened these in maxigene-transfected HEK293T cells. Candidate AONs able to promote exon inclusion were selected for further testing in patient-derived photoreceptor precursor cells. Surprisingly, no robust splicing modulation was observed in this model system. Overall, this research helped to adequately characterize the splicing alteration caused by the c.4253+43G>A variant, although future development of AON-mediated exon inclusion therapy for ABCA4 is needed.

Background Aims: Age-related macular degeneration (AMD) is the most common cause of blindness in elderly patients within developed countries, affecting more than 190 million worldwide. In AMD, the retinal pigment epithelial (RPE) cell layer progressively degenerates, resulting in subsequent loss of photoreceptors and ultimately vision. There is currently no cure for AMD, but therapeutic strategies targeting the complement system are being developed to slow the progression of the disease., Methods: Replacement therapy with pluripotent stem cell-derived (hPSC) RPEs is an alternative treatment strategy. A cell therapy product must be produced in accordance with Good Manufacturing Practices at a sufficient scale to facilitate extensive pre-clinical and clinical testing. Cryopreservation of the final cell product is therefore highly beneficial, as the manufacturing, pre-clinical and clinical testing can be separated in time and location., Results: We found that mature hPSC-RPE cells do not survive conventional cryopreservation techniques. However, replating the cells 2-5 days before cryopreservation facilitates freezing. The replated and cryopreserved hPSC-RPE cells maintained their identity, purity and functionality as characteristic RPEs, shown by cobblestone morphology, pigmentation, transcriptional profile, RPE markers, transepithelial resistance and pigment epithelium-derived factor secretion. Finally, we showed that the optimal replating time window can be tracked noninvasively by following the change in cobblestone morphology., Conclusions: The possibility of cryopreserving the hPSC-RPE product has been instrumental in our efforts in manufacturing and performing pre-clinical testing with the aim for clinical translation., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Stargardt macular dystrophy (Stargardt disease; STGD1; OMIM 248200) is the most prevalent inherited macular dystrophy. STGD1 is an autosomal recessive disorder caused by multiple pathogenic sequence variants in the large ABCA4 gene (OMIM 601691). Major advances in understanding both the clinical and molecular features, as well as the underlying pathophysiology, have culminated in many completed, ongoing and planned human clinical trials of novel therapies.The aims of this concise review are to describe (1) the detailed phenotypic and genotypic characteristics of the disease, multimodal imaging findings, natural history of the disease, and pathogenesis, (2) the multiple avenues of research and therapeutic intervention, including pharmacological, cellular therapies and diverse types of genetic therapies that have either been investigated or are under investigation and (3) the exciting novel therapeutic approaches on the translational horizon that aim to treat STGD1 by replacing the entire 6.8 kb ABCA4 open reading frame., Competing Interests: Competing interests: Disclosures/Conflicts of Interest: KF: Consultant (category C): Astellas Pharma, Kubota Pharmaceutical, Acucela, Novartis, Janssen, Sanofi, NightstaRx, Stargazer, SalioGen Therapeutics, Belite Bio, Alnylam, Restore Vision, FRESTKF: Clinical trial/Research support (category F): National Institute for Health and Care Research, Foundation Fighting Blindness, Janssen, Novartis, Janssen, AstellasPY: Consultant (category C): 4D Molecular Therapeutics, Adverum, AGTC, Annexon Bio, EcoR1, Exegenesis Bio, ExpertConnect, Foundation Fighting Blindness (SAB), Guidepoint, Iveric Bio, Janssen, MeiraGTx, Nanoscope Therapeutics (SAB), Otonomy, ProQR, Saliogen Therapeutics, TeamedOn, VederePY: Clinical trial/Research support (category F): 4D Molecular Therapeutics, Acucela, Atsena, AGTC, Biogen, Editas, Foundation Fighting Blindness, Iveric bio, Ocugen, ProQR, Reneuron, Sanofi, SparkNW: Consultant (category C): Complement Therapeutics, Nidek, SalioGen Therapeutics, Stealth, Syncona, TopconNW: Clinical trial/Research support (category F): Carl Zeiss Meditec, Heidelberg, NidekNW: N Waheed is a board member of Iolyx Therapeutics, a shareholder in Ocudyne, and a previous shareholder of Gyroscope Therapeutics. JH, JTL and CC: JH and JTL are currently full-time employees and stock option holders of SalioGen Therapeutics. C Clary is a former employee of SalioGen Therapeutics.DC: D Curtiss is a full-time employee and stock option holder of AGTC. YL, YF-Y: YL and YF-Y have no conflicts of interest to disclose. MM: Consultant (category C): Acucela, MeiraGTx, Janssen, Stargazer, Claris Bio, SalioGen Therapeutics, Belite Bio and Alnylam. MM holds equity in MeiraGTx., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in the elderly, and anti-vascular endothelial growth factor (VEGF) therapy is currently the primary treatment approach. However, the real-world effectiveness of nAMD treatment is not always satisfactory and faces various challenges. Frequent administration and follow-up burdens can lead to decreased patient compliance during long-term treatment, resulting in suboptimal outcomes. Some lesions exhibit poor or no response to anti-VEGF treatment, leading to difficulties in maintaining or even declining visual acuity. Factors such as lesion fibrosis and tissue atrophy can contribute to visual deterioration. Therefore, standardizing and individualizing treatment plans, along with enhancing comprehensive monitoring and management throughout the disease course, are crucial improvement measures. The evidence-based guidelines for diagnosis and treatment of age-related macular degeneration in China, released in 2023, provide guidance for standardized clinical diagnosis and treatment. Meanwhile, research and development of new drugs and administration methods are anticipated for the future.

Objectives: Remote monitoring of health has the potential to reduce the burden to patients of face-to-face appointments and make healthcare more efficient. Apps are available for patients to self-monitor vision at home, for example, to detect reactivation of age-related macular degeneration (AMD). Describing the challenges when implementing apps for self-monitoring of vision at home was an objective of the MONARCH study to evaluate two vision-monitoring apps on an iPod Touch (Multibit and MyVisionTrack)., Design: Diagnostic Test Accuracy study., Setting: Six UK hospitals., Methods: The study provides an example of the real-world implementation of such apps across health sectors in an older population. Challenges described include the following: (1) frequency and reason for incoming calls made to a helpline and outgoing calls made to participants; (2) frequency and duration of events responsible for the tests being unavailable; and (3) other technical and logistical challenges., Results: Patients (n=297) in the study were familiar with technology; 252/296 (85%) had internet at home and 197/296 (67%) had used a smartphone. Nevertheless, 141 (46%) called the study helpline, more often than anticipated. Of 435 reasons for calling, all but 42 (10%) related to testing with the apps or hardware, which contributed to reduced adherence. The team made at least one call to 133 patients (44%) to investigate why data had not been transmitted. Multibit and MyVisionTrack apps were unavailable for 15 and 30 of 1318 testing days for reasons which were the responsibility of the app providers. Researchers also experienced technical challenges with a multiple device management system. Logistical challenges included regulations for transporting lithium-ion batteries and malfunctioning chargers., Conclusions: Implementation of similar technologies should incorporate a well-resourced helpline and build in additional training time for participants and troubleshooting time for staff. There should also be robust evidence that chosen technologies are fit for the intended purpose., Trial Registration Number: ISRCTN79058224., Competing Interests: Competing interests: REH reports attendance at Roche Digital Health Advisory Meeting July 2019. She also received partial PhD Studentship funding from Okko Health 2021 for home monitoring of Diabetic Retinopathy. SS reports grants from Boehringer Ingleheim, receiving consulting fees from Boehringer Ingleheim, Novartis, Apellis, Bayer, Oculis, Oxurion, Roche, and Biogen. She also received payment or honoraria from Boehringer Ingleheim and Bayer, support for attending meetings from Bayer and participation in an advisory board with Bayer. She is also a Macular Society Trustee (unpaid). TP reports grants from Boehringer Ingelheim and Novartis; receiving consulting fees from Boehringer Ingelheim, Novartis, Apellis, Bayer, Oxurion, Roche, and Sandoz. She also received payment or honoraria (speakers fee/and/or advisory board) from Boehringer Ingelheim, Bayer, Roche, Apellis, Sandoz, Heidelberg, Zeiss, Optos. PCK reports software support from Vital Art and Science who produced the My Vision Track App. AL reports receiving consulting fees from and owning stock or stock options of Gyroscope Therapeutics. RW, SRO'C, EAG, EW, CT, BJLB, CAR and BCR have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Retinal degenerative disorders (RDDs) cause vision loss by damaging retinal neurons and photoreceptors, affecting individuals of all ages. Cell-based therapy has emerged as an effective approach for the treatment of RDDs with promising results. This meta-analysis aims to comprehensively evaluate the efficacy of cell therapy in treating age-related macular degeneration (AMD), retinitis pigmentosa (RP), and Stargardt macular degeneration (SMD) as the most prevalent RDDs., Methods: PubMed, Scopus, Web of Science, and Embase were searched using keywords related to various retinal diseases and cell therapy treatments until November 25th, 2023. The studies' quality was evaluated using the Joanna Briggs Institute's (JBI) checklist for quasi-experimental studies. Visual acuity measured as LogMAR score was used as our main outcome. A three-level random-effect meta-analysis was used to explore the visual acuity in patients who received cell-based therapy. Heterogeneity among the included studies was evaluated using subgroup and sensitivity analyses. Moreover, meta-regression for the type of cells, year of publication, and mean age of participants were performed., Results: Overall, 8345 studies were retrieved by the search, and 39 met the eligibility criteria, out of which 18 studies with a total of 224 eyes were included in the meta-analysis. There were 12 studies conducted on AMD, 7 on SMD, and 2 on RP. Cell therapy for AMD showed significant improvement in LogMAR (p < 0.05). Also, cell therapy decreased the LogMAR score in SMD and RP (p < 0.01 and p < 0.0001, respectively). Across all conditions, no substantial publication bias was detected (p < 0.05)., Conclusion: The findings of the study highlight that the application of cell therapy can enhance the visual acuity in AMD, SMD, and RP., (© 2024. The Author(s).)

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among the elderly in the developed world. Whilst AMD is a multifactorial disease, the involvement of the complement system in its pathology is well documented, with single-nucleotide polymorphisms (SNPs) in different complement genes representing an increased risk factor. With several complement inhibitors explored in clinical trials showing limited success, patients with AMD are still without a reliable treatment option. This indicates that there is still a gap of knowledge in the functional implications and manipulation of the complement system in AMD, hindering the progress towards translational treatments. Since the discovery of the CRISPR/Cas system and its development into a powerful genome engineering tool, the field of molecular biology has been revolutionised. Genetic variants in the complement system have long been associated with an increased risk of AMD, and a variety of haplotypes have been identified to be predisposing/protective, with variation in complement genes believed to be the trigger for dysregulation of the cascade leading to inflammation. AMD-haplotypes (SNPs) alter specific aspects of the activation and regulation of the complement cascade, providing valuable insights into the pathogenic mechanisms of AMD with important diagnostic and therapeutic implications. The effect of targeting these AMD-related SNPs on the regulation of the complement cascade has been poorly explored, and the CRISPR/Cas system provides an ideal tool with which to explore this avenue. Current research concentrates on the association events of specific AMD-related SNPs in complement genes without looking into the effect of targeting these SNPs and therefore influencing the complement system in AMD pathogenesis. This review will explore the current understanding of manipulating the complement system in AMD pathogenesis utilising the genomic manipulation powers of the CRISPR/Cas systems. A number of AMD-related SNPs in different complement factor genes will be explored, with a particular emphasis on factor H (C FH ), factor B (C FB ), and complement C3 ( C3 ).

Age-related macular degeneration (AMD) is a severe retinal disease that causes irreversible visual loss and blindness in elderly populations worldwide. The pathological mechanism of AMD is complex, involving the interactions of multiple environmental and genetic factors. A poor understanding of the disease leads to limited treatment options and few effective prevention methods. The discovery of autoantibodies in AMD patients provides an opportunity to explore the pathogenesis and treatment direction of the disease. This review focuses on the mitochondria-associated autoantibodies and summarizes the functional roles of mitochondria under physiological conditions and their alterations during the pathological states. Additionally, it discusses the crosstalk between mitochondria and other organelles, as well as the mitochondria-related therapeutic strategies in AMD.

Background: Age-related macular degeneration (AMD) is an irreversible eye disease that can cause blurred vision. Regular exercise has been suggested as a therapeutic strategy for treating AMD, but how exercise improves AMD is not yet understood. This study investigated the protective effects of developmental endothelial locus-1 (DEL-1), a myokine upregulated during exercise, on endoplasmic reticulum (ER) stress-induced injury in retinal pigment epithelial cells., Methods: We evaluated the levels of AMPK phosphorylation, autophagy markers, and ER stress markers in DEL-1-treated human retinal pigment epithelial cells (hRPE) using Western blotting. We also performed cell viability, caspase 3 activity assays, and autophagosome staining., Results: Our findings showed that treatment with recombinant DEL-1 dose-dependently reduced the impairment of cell viability and caspase 3 activity in tunicamycin-treated hRPE cells. DEL-1 treatment also alleviated tunicamycin-induced ER stress markers and VEGF expression. Moreover, AMPK phosphorylation and autophagy markers were increased in hRPE cells in the presence of DEL-1. However, the effects of DEL-1 on ER stress, VEGF expression, and apoptosis in tunicamycin-treated hRPE cells were reduced by AMPK siRNA or 3-methyladenine (3-MA), an autophagy inhibitor., Conclusions: Our study suggests that DEL-1, a myokine, may have potential as a treatment strategy for AMD by attenuating ER stress-induced injury in retinal pigment epithelial cells., (© 2024. The Author(s).)

Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are vascular diseases with high prevalence, ranking among the leading causes of blindness and vision loss worldwide. Despite being effective, current treatments for AMD and DR are burdensome for patients and clinicians, resulting in suboptimal compliance and real risk of vision loss. Thus, there is an unmet need for long-lasting alternatives with improved safety and efficacy. Adeno-associated virus (AAV) is the leading vector for ocular gene delivery, given its ability to enable long-term expression while eliciting relatively mild immune responses. Progress has been made in AAV-based gene therapies for not only inherited retinal diseases but also acquired conditions with preclinical and clinical studies of AMD and DR showing promising results. These studies have explored several pathways involved in the disease pathogenesis, as well as different strategies to optimise gene delivery. These include engineered capsids with enhanced tropism to particular cell types, and expression cassettes incorporating elements for a targeted and controlled expression. Multiple-acting constructs have also been investigated, in addition to gene silencing and editing. Here, we provide an overview of strategies employing AAV-mediated gene delivery to treat AMD and DR. We discuss preclinical efficacy studies and present the latest data from clinical trials for both diseases., (© 2023. The Author(s).)

The aim of this article is to explain age-related macular degeneration (AMD) and how it impacts on the wellbeing of patients in the community setting. It explores the anatomy and physiology associated with AMD, its symptoms and treatment, and goes on to discuss related nursing care.

Geographic atrophy (GA) is a progressive and irreversible retinal disease with no comprehensive recommendations for diagnosis or monitoring. We used a Delphi approach to determine consensus in key areas around diagnosis and management of GA. A steering committee of eight retina specialists developed two sequential online surveys administered to eye care professionals (ECPs). Consensus was defined as agreement by ≥ 75% of respondents. Up to 177 ECPs from eight countries completed one or both surveys. Consensus was achieved in several topics related to diagnostic imaging, including the use of optical coherence tomography, and the urgent need for treatments and beneficial interventions to reduce the associated burden. Currently, low-vision aids and smoking cessation are considered the most beneficial interventions. We demonstrate consensus for diagnosis and management of patients with GA including best practices in patient identification and monitoring, and unmet needs. [ Ophthalmic Surg Lasers Imaging Retina 2023;54:589-598.] .

The COVID-19 pandemic has led to both intentional and unintentional care delay among age-related neovascular macular degeneration (nvAMD) patients. Prior studies have demonstrated that patients who discontinue nvAMD treatment for prolonged intervals are at high risk for vision loss, but less is known regarding shorter-term delay, such as during the height of the pandemic. Previous studies have looked at COVID-19 related delay in care and have shown a loss of visual acuity (VA) among these patients, but studies are limited by short follow-up or insufficient comparisons. This was an observational cohort study of nvAMD patients from March 1, 2019, through July 1, 2021, who experienced care delay. VA was modeled using a linear longitudinal mixed-effects model comparing historic data pre-lockdown to data post-lockdown. Covariates included baseline anatomic variables, demographic variables, and time intervals (treatment interval, delay interval). Secondary anatomic and treatment outcomes were modeled using a multilevel binary logistic regression model. 163 eyes among 116 patients were included. Initial longitudinal mixed-effects models found that although overall VA decreased at a yearly rate, when comparing pre-lockdown and post-lockdown time periods, VA slopes were not statistically different. Single-covariate longitudinal models showed that age, sex, and delay interval significantly affected VA slope. The multivariate longitudinal model found that a longer delay interval significantly decreased rate of VA loss. Multilevel binary logistic regression models showed a significant increase in odds of anti-VEGF treatment, presence of subretinal fluid, and macular hemorrhages in the post-lockdown period. Overall, when compared to historic data, rate of VA loss among our cohort did not vary significantly in pre-versus post-lockdown time periods, although treatment and anatomic variables did worsen post-lockdown suggesting that patients may be appropriately delayed but this comes at the risk of increased need for treatment., (© 2023. Springer Nature Limited.)

Introduction and Objective: Healthcare resources optimization is crucial to assume the growing demand of neovascular age-related macular degeneration (nAMD). This work provides guidelines and support so that each hospital can lead its change management., Methods: The OPTIMUS project (n=10 hospitals) was based on face-to-face interviews with the key staff of the ophthalmology services, and alignment with the main responsible for each centre (nominal group) to identify potential needs for improving nAMD. The OPTIMUS nominal group was expanded to 12 centres (eVOLUTION). Through different remote work sessions, different guides and tools were defined and developed to implement proactive treatment strategies, one-step treatment administration and potential for remote visits (eConsult) in nAMD., Results: The information collected from the OPTIMUS interviews and working groups (n=10 centres) defined roadmaps to promote the development of protocols and proactive treatment strategies, including healthcare workload optimization and one-stop treatment administration in nAMD. With eVOLUTION, processes and tools were developed to promote eConsult: (i) healthcare burden calculator; (ii) definition of potential patients for telematic management; (iii) definition of nAMD management archetypes; (iv) definition of processes for implementation of eConsult by archetype; and (v) key performance indicators for changing evaluation., Conclusions: Managing change is an internal task that requires an adequate diagnosis of processes and feasible implementation roadmaps. OPTIMUS and eVOLUTION provide the basic tools for an autonomous advance of hospitals in the optimization of AMD management, with the available resources., (Copyright © 2023. Publicado por Elsevier España, S.L.U.)

Purpose: Age-related macular degeneration (AMD) is a major cause of vision loss globally. Patients with AMD may not always understand or retain the information about AMD communicated by their eyecare practitioner. This study aims to explore the characteristics of effective health communication for AMD, from both patients' and eyecare practitioners' perspectives. The purpose is to provide a foundation for understanding how health communication for AMD could potentially be improved in the future., Methods: A total of 10 focus groups involving 17 patients with AMD and 17 optometrists were conducted via web conferencing. Each session was audio-recorded, transcribed and analysed using the Grounded Theory Methodology., Results: The five themes identified are as follows: (1) materials' quality, (2) materials' relevance, (3) contextualising for the individual, (4) contextualising for the disease and (5) support network. Participants expressed concern about the unrealistic yet common depiction of vision loss in AMD as a black patch overlying common visual scenes. They also preferred education materials tailored to a specific disease stage and the regular opportunity to ask or answer questions. Longer appointment durations and peer support (from family, friends or others with AMD) were also valued., Conclusion: Optometrists are encouraged to focus on three over-arching dimensions when counselling patients with AMD in routine clinical practice: (1) curating and using disease and stage-specific, impactful education materials, (2) their chairside verbal communication techniques and (3) AMD-specific opportunities for care coordination among patient family and friends, peers and other multidisciplinary members of the care support team., (© 2023 The Authors. Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.)

Visual impairment and blindness are a growing public health problem as they reduce the life quality of millions of people. The management and treatment of these diseases represent scientific and therapeutic challenges because different cellular and molecular actors involved in the pathophysiology are still being identified. Visual system components, particularly retinal cells, are extremely sensitive to genetic or metabolic alterations, and immune responses activated by local insults contribute to biological events, culminating in vision loss and irreversible blindness. Several ocular diseases are linked to retinal cell loss, and some of them, such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and diabetic retinopathy, are characterized by pathophysiological hallmarks that represent possibilities to study and develop novel treatments for retinal cell degeneration. Here, we present a compilation of revisited information on retinal degeneration, including pathophysiological and molecular features and biochemical hallmarks, and possible research directions for novel treatments to assist as a guide for innovative research. The knowledge expansion upon the mechanistic bases of the pathobiology of eye diseases, including information on complex interactions of genetic predisposition, chronic inflammation, and environmental and aging-related factors, will prompt the identification of new therapeutic strategies.

Retinal pigment epithelium (RPE) is a critical cell monolayer forming the blood-retina-barrier (BRB) and a permeable bridge between the choriocapillaris and the retina. RPE is also crucial in maintaining photoreceptor function and for completing the visual cycle. Loss of the RPE is associated with the development of degenerative diseases like age-related macular degeneration (AMD). To treat diseases like AMD, pluripotent stem cell-derived RPE (pRPE) has been recently explored extensively as a regenerative module. pRPE like other ectodermal tissues requires specific lineage differentiation and long-term in vitro culturing for maturation. Therefore, understanding the differentiation process of RPE could be useful for stem cell-based RPE derivation. Developing pRPE-based transplants and delivering them into the subretinal space is another aspect that has garnered interest in the last decade. In this review, we discuss the basic strategies currently employed for stem cell-based RPE derivation, their delivery, and recent clinical studies related to pRPE transplantation in patients. We have also discussed a few limitations with in vitro RPE culture and potential solutions to overcome such problems which can be helpful in developing functional RPE tissue., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Age-related macular degeneration (AMD), particularly wet AMD characterised by choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. The hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway contributes to CNV pathogenesis. Previous gene editing research indicated that disrupting these genes in retinal pigment epithelial cells could have a preventive effect on CNV progression. However, no studies have yet been conducted using gene editing to disrupt VEGF signalling after CNV induction for therapeutic validation, which is critical to the clinical application of wet AMD gene editing therapies., Method: Here, we employed the single-adeno-associated virus-mediated Nme 2 Cas9 to disrupt key molecules in VEGF signalling, Hif1α, Vegfa and Vegfr2 after inducing CNV and estimated their therapeutic effects., Results: We found that Nme 2 Cas9 made efficient editing in target genes up to 71.8% post 11 days in vivo. And only Nme 2 Cas9-Vegfa treatment during the early stage of CNV development reduced the CNV lesion area by 49.5%, compared to the negative control, while Nme 2 Cas9-Hif1α or Nme 2 Cas9-Vegfr2 treatment did not show therapeutic effect. Besides, no off-target effects were observed in Nme 2 Cas9-mediated gene editing in vivo., Conclusions: This study provides proof-of-concept possibility of employing Nme 2 Cas9 for potential anti-angiogenesis therapy in wet AMD., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Regenerative medicine is a great hope for patients suffering from diseases for which no effective treatment is available. With the creation of induced pluripotent stem cells (iPSCs) in 2006, research and development has accelerated expeditiously, reaching a practical stage worldwide. The iPSC-regenerative medicine in ophthalmology is one of the pioneers, which has kicked off clinical application ahead of other fields owing to its advantages. The clinical safety issues of iPSC-derived retinal pigment epithelial (iPSC-RPE) transplantation for exudative age-related macular degeneration have been addressed to a certain extent. Preparations are being made for the next clinical study based on the improvement of its therapeutic effects and expansion of indications globally. Steady progress toward the practical applications of regenerative medicine for the treatment of retinal disorders is expected in the future while strengthening global cooperation amid various research areas, clinical fields, and regulations., (Copyright © 2023 Cold Spring Harbor Laboratory Press; all rights reserved.)

Adeno-associated virus (AAV)-based gene therapy has been shown to be safe and effective in numerous animal models and clinical trials for various ophthalmic diseases. Stargardt disease (STGD1; MIM #248200) is the most common autosomal recessive macular dystrophy disease, and the most common form is caused by mutations in the ABCA4 gene, a gene with 6.8 kb coding sequence. Split intein approaches increase the capacity of dual AAV gene therapy, but at the cost of reduced protein expression, which may be insufficient to achieve a therapeutic effect. In this study, we designed various dual split intein ABCA4 vectors and showed that the efficiency of expression of full-length ABCA4 protein is dependent on combinations of types and split sites of the intein system. The most efficient vectors were identified through in vitro screening, and a novel dual AAV8-ABCA4 vector was constructed and subsequently proven to express full-length ABCA4 protein at a high level, reducing bisretinoid formation and correcting the visual function of ABCA4-knockout mice. Furthermore, we evaluated therapeutic effects of different dosages by subretinal injection in mice model. Both therapeutic effects and safety were guaranteed under the treatment of 1.00 × 10 9 GC/eye. These results support the optimized dual AAV8-ABCA4 approach in future clinical translation for treatment of Stargardt disease.

Purpose: Evidence supports the clinical decision-making ability of primary care optometrists with additional qualifications in the identification of eligibility criteria for the certification of vision impairment (CVI). Welsh Government policy is driving pathway change to enable these optometrists to perform CVI. This qualitative study explores the views of people with VI due to dry age-related macular degeneration (AMD) on this pathway change., Methods: Nine people with VI due to dry AMD, attending Macular Society support groups, participated. Individual semi-structured interviews were conducted and analysed concurrently using thematic analysis., Results: Five major themes were identified: (1) living with dry AMD, (2) experience of eye care provision, (3) knowledge of CVI, (4) provision of information and (5) CVI in primary care. Participants consistently highlighted the need for the provision of accessible information regarding the certification pathway, dry AMD and the optometrist's role in the provision of eye health care. Information needs to be available prior to the diagnosis of an eye disease, rather than only from the point of diagnosis or where the vision reaches the level required for certification., Conclusion: The findings support the provision of CVI within primary eye care while highlighting areas of importance in pathway development. These include the provision of accessible information prior to, at the point of and following the diagnosis of an eye condition. Information provided needs to extend to the awareness of the role of the optometrist in the provision of eye care, and public health awareness of modifiable risk factors, which will influence the possibility of disease development in later life. The findings provide information that will be useful to those responsible for the provision of CVI within primary care., (© 2023 College of Optometrists.)

Introduction: Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the United Kingdom. It has a wide-ranging detrimental impact on daily living, including impairment of functional ability and quality of life. Assistive technology designed to overcome this impairment includes wearable electronic vision enhancement systems (wEVES). This scoping review assesses the usefulness of these systems for people with AMD., Methods: Four databases (Cumulative Index to Nursing and Allied Health Literature, PubMed, Web of Science and Cochrane CENTRAL) were searched to identify papers that investigated image enhancement with a head-mounted electronic device on a sample population that included people with AMD., Results: Thirty-two papers were included: 18 studied the clinical and functional benefits of wEVES, 11 investigated use and usability and 3 discussed sickness and adverse effects., Conclusions: Wearable electronic vision enhancement systems provide hands-free magnification and image enhancement producing significant improvements in acuity, contrast sensitivity and aspects of laboratory-simulated daily activity. Adverse effects were infrequent, minor and spontaneously resolved with the removal of the device. However, when symptoms arose, they sometimes persisted with continued device usage. There are multi-factorial influences and a diversity of user opinions on promotors to successful device use. These factors are not exclusively driven by visual improvement and incorporate other issues including device weight, ease of use and inconspicuous design. There is insufficient evidence of any cost-benefit analysis for wEVES. However, it has been shown that a user's decision to make a purchase evolves over time, with their estimates of cost falling below the retail price of the devices. Additional research is needed to understand the specific and distinct benefits of wEVES for people with AMD. Further patient-centred research should assess the benefits of wEVES in user-led activities when directly compared with alternative coping strategies, allowing professionals and users to make better prescribing and purchasing decisions., (© 2023 The Authors. Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.)